Identification of Intragenic Exon Deletions and Duplication of TCF12 by Whole Genome or Targeted Sequencing as a Cause of TCF12-Related Craniosynostosis

• Published in: Human mutation Vol. 37; no. 8; pp. 732 - 736
• Main Authors: Goos, Jacqueline A.C., Fenwick, Aimee L., Swagemakers, Sigrid M.A., McGowan, Simon J., Knight, Samantha J.L., Twigg, Stephen R.F., Hoogeboom, A. Jeannette M., van Dooren, Marieke F., Magielsen, Frank J., Wall, Steven A., Mathijssen, Irene M.J., Wilkie, Andrew O.M., van der Spek, Peter J., van den Ouweland, Ans M.W.
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01-08-2016; Hindawi Limited; John Wiley and Sons Inc
• Subjects: Base Sequence; Basic Helix-Loop-Helix Transcription Factors - genetics; Birth defects; Brain; Brief Report; Brief Reports; Craniosynostoses - genetics; exon duplication; Exons; Female; Genetic Predisposition to Disease; Genomes; Humans; intragenic exon deletion; Male; Mutation; Pedigree; rearrangements; Sequence Analysis, DNA - methods; Sequence Deletion; Tandem Repeat Sequences; TCF12-related craniosynostosis; exon duplication; intragenic exon deletion; TCF12-related craniosynostosis; rearrangements
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.23010

ABSTRACT
TCF12‐related craniosynostosis can be caused by small heterozygous loss‐of‐function mutations in TCF12. Large intragenic rearrangements, however, have not been described yet. Here, we present the identification of four large rearrangements in TCF12 causing TCF12‐related craniosynostosis. Whole‐genome sequencing was applied on the DNA of 18 index cases with coronal synostosis and their family members (43 samples in total). The data were analyzed using an autosomal‐dominant disease model. Structural variant analysis reported intragenic exon deletions (of sizes 84.9, 8.6, and 5.4 kb) in TCF12 in three different families. The results were confirmed by deletion‐specific PCR and dideoxy‐sequence analysis. Separately, targeted sequencing of the TCF12 genomic region in a patient with coronal synostosis identified a tandem duplication of 11.3 kb. The pathogenic effect of this duplication was confirmed by cDNA analysis. These findings indicate the importance of screening for larger rearrangements in patients suspected to have TCF12‐related craniosynostosis.
The phenotype of the index patients, their pedigrees (sequenced individuals in red boxes, mutation carriers indicated by asterisks), the method used to identify the rearrangement, and, lastly, their position. BCS = bicoronal suture synostosis, ICP = intracranial pressure, LCS = left coronal suture synostosis, M = metopic suture, PAN = pansynostosis, RCS = right coronal suture synostosis, and WGS = whole genome sequencing.